OTC Naloxone May Get Another Push From US FDA As Agency Prepares Novel Switch Proposed Rule
Executive Summary
Financial model is not adequate right now, FDA Commissioner Robert Califf says, so the agency may make regulatory changes to motivate sponsors.
Naloxone manufacturers could receive another regulatory nudge from the US Food and Drug Administration to produce an OTC nasal spray of the opioid overdose medication.
Commissioner Robert Califf said the agency is having “serious discussions right now about what we can do to exert some changes compared to the usual way of doing business to make this happen.”
“I think the problem is that the financial model doesn’t appear to be working for the companies,” Califf said 29 April during the Association of Health Care Journalists Health Journalism 2022 conference.
Califf suggested OTC switch regulations could be used to motivate more companies to make the change.
“We can’t order companies to [go] over-the-counter, but what we’re doing now is not working the way we’d like it to,” he said. “There are specifications for how you convert to over-the-counter and we’re looking closely at what those specs are to see what we can do to change the equation so there’s more motivation to make it happen.”
While expanding naloxone access has extraordinary potential in the US, the FDA, since launching its NSURE initiative – "nonprescription safe use regulatory extension" – in 2012, has been considering a rulemaking to accelerate OTC switches by allowing new drug application sponsors to use extra-label information to guide consumers through self-diagnosis and -selection of a drug. Califf noted he would support making progress on the "Nonprescription Drug Product With an Additional Condition for Nonprescription Use" proposed rule during his confirmation process. (Also see "Making Progress On Novel OTC Switch Rulemaking Has FDA Commissioner Nominee Califf’s Attention" - HBW Insight, 12 Jan, 2022.)
A potential OTC switch for naloxone could significantly increase access, one of the goals of the FDA’s campaign to fight the opioid epidemic. The agency nudged potential new drug application sponsors in 2018 when it took an unprecedented step of sponsoring a study for a model Drug Facts label sponsors of new drug applications to switch the ingredient could use.
"There are specifications for how you convert to over-the-counter and we’re looking closely at what those specs are to see what we can do to change the equation so there’s more motivation to make it happen.” – FDA Commissioner Califf
The FDA said in 2019 that sponsors were interested in switching products but issues including cost and stigma remain concerns. (Also see "FDA Has Model Drug Facts Labels For OTC Naloxone, Wants Switch Proposals" - HBW Insight, 17 Jan, 2019.)
Harm Reduction Therapeutics LLC, a non-profit company, has completed necessary studies and plans to submit a switch proposal for a naloxone nasal spray later in 2022. Its Phase I trial of its 3-mg nasal spray delivering an atomized form of 0.1-mL naloxone demonstrated the bioavailability of the formulation was bioequivalent to 0.4-mg intramuscular naloxone at 2.5 minutes and at 5 minutes after administration, (Also see "HRT Reports 'Remarkable Achievement' In OTC Naloxone Phase 1 Clinical Trial Results" - HBW Insight, 1 Mar, 2022.)
In a recent online conference on expanding naloxone access, HRT co-founder and CEO Michael Hufford framed his comments in acknowledging the FDA’s difficult work and heavy workload in reviewing and evaluating NDAs and other applications, but was critical of agency officials’ response to the firm's outreach on submitting a naloxone OTC switch proposal, including denying Pittsburgh-based HRT’s request for expedited review of its switch NDA in the agency’s fast track program. (Also see "Drivers For Allowing OTC Naloxone In US Include Social Justice As Well As Public Health Need" - HBW Insight, 31 Mar, 2022.)
The bankruptcy proceeding for opioid maker Purdue Pharma L.P. made funding available for the HRT phase I study. (Also see "OTC Naloxone Nasal Spray Biocompatibility Study Funded In US From Purdue Pharma Bankruptcy" - HBW Insight, 23 Jun, 2020.)
Purdue entered bankruptcy amid ongoing litigation related to the opioid epidemic. A settlement worth several billion dollars was reached with multiple states and other jurisdictions. (Also see "Nationwide Opioid Settlement May Provide Path For Other Manufacturers" - Pink Sheet, 25 Feb, 2022.)
Instructions For Use Critical
Califf did not offer specifics on ideas the FDA is considering to encourage OTC naloxone switch applications. But asked whether the agency would forcibly move a naloxone formulation to OTC, Califf said it must be sure that consumers can safely use the products.
“This gets back to being confident that the instructions of use are something that can be followed adequately by the person who’s purchasing it over the counter, which is a little different for injecting something than taking a pill,” he said. “You’re at the crux of the issue where I think there are things we can do and we’re very seriously working on it.”
Sponsors of complex generic drugs often run into approval problems because of questions about devices delivering the pharmaceutical ingredients. Device variations are allowed, but cannot impact patient safety. (Also see "Generic Combination Products May Be Permitted Delivery Device Variations" - Pink Sheet, 4 Jun, 2017.)
The upcoming prescription drug user fee reauthorization will include performance goals for human factors studies, which often must be submitted to prove device equivalence, as well as deadlines for new guidances on the trials. (Also see "Sentinel Could Be Used For Pregnancy Safety Studies Under PDUFA VII" - Pink Sheet, 20 Jan, 2021.)
Similarly, proposed and potential OTC switches have been shelved after results of actual use studies weren't strong enough to show that consumers would accurately self-select and use a drug without the intervention of a health care professional; an OTC naloxone nasal spray application would have to convince the FDA, and likely an advisory committee, that trials show consumers would use the product correctly. (Also see "With Limits Of OTC Drug Fact Label ‘Simple Boxes,' Complicated Conditions Remain Rx-Only In US" - HBW Insight, 13 Jun, 2021.)
As far as forcing an OTC switch, the agency has said it has authority under the 1984 Drug Price Competition and Patent Term Restoration Act – Public Law 98-417 – also known as the Hatch-Waxman Amendment, to compel making available for nonprescription sales drug ingredients currently available Rx-only which it considers should be available OTC to meet a public health need.
Drug firms contest the FDA’s assertion of the authority, and the agency hasn’t exercised it. However, its consideration of forcing OTC switches of low- and non-sedating antihistamines prompted pharma firms to file switch NDAs for the products starting in 2002. (Also see "Antihistamine Forced Switch Proposal Returns In Citizen Petition" - HBW Insight, 26 Mar, 2007.)
OTC Switch Part Of Wider FDA Opioid Campaign
In addition to pushing for an OTC switch, the FDA also clarified that non-profits and other organizations could distribute generic injectable naloxone in communities.
Some stakeholders had suggested that labeling for the product does not make clear that the non-medical professionals could use it. The FDA made a public statement rather than changing the label. (Also see "US FDA's Words Matter: Sharpless Says Injectable Naloxone OK For Community Distribution" - Pink Sheet, 25 Sep, 2019.)
The agency also considered mandating naloxone be co-prescribed along with any opioid, but decided including in labeling advice for discussions between providers and patients about obtaining naloxone would suffice. Economists estimated the US health system would incur a substantial cost burden if providing naloxone with opioid prescriptions was mandated. (Also see "Opioid Labeling Instructions On Naloxone Are Compromise In Co-Prescribing Debate" - Pink Sheet, 26 Jul, 2020.)
FDA officials also want to change opioid prescribing habits by mandating training through the opioid risk evaluation and mitigation strategy (Also see "Opioid Prescriber Education Program May Become Mandatory; FDA Cites Failures In Voluntary System" - Pink Sheet, 8 Sep, 2021.), and requiring dispensing opioid pills in blister packs. Neither idea is popular with stakeholders. (Also see "Opioid Blister Packs Need Study Before Mandate, Groups Urge " - Pink Sheet, 11 Aug, 2019.)
Additionally, sponsors could be mandated to provide mail-back envelopes so patients could return unused pills for disposal. (Also see "US FDA Considering Opioid Mail-Back Envelope Mandate, But Industry Has Heard This Before" - Pink Sheet, 21 Apr, 2022.)
During his confirmation process in 2021, Califf promised to reconsider whether opioid labels should be changed or withdrawn. (Also see "Califf Says Opioid Labeling Changes, Withdrawals Still Possible" - Pink Sheet, 13 Apr, 2022.) He also said the agency could seek authority from Congress to require superiority data to approve new opioid products.